In recent years, the understanding of regulatory T cell (T
cell) biology has expanded considerably. Key observations have challenged the traditional definition of T
cells and have provided insight ...into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of T
cell instability, T
cell plasticity and tissue-specific T
cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of T
cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases.
Foxp3+ T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. ...Here we identified Foxp3+ T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT+ Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.
•TIGIT defines a distinct Foxp3+ Treg cell subset•TIGIT induces transcription and secretion of the effector molecule Fgl2 in Treg cells•TIGIT+ Treg cells suppress proinflammatory Th1 and Th17 not Th2 cell responses•Selective suppression by TIGIT+ Treg cells is Fgl2 dependent
Highlights • Human CD4+ T cells can display a high grade of plasticity. • Th17 cells can adapt Th1- and Th2-type phenotypes. • FoxP3+ Tregs can differentiate into Th1- and Th17-like cells. • These ...mechanisms may play a role in autoimmune diseases like MS.
Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with ...temozolomide chemotherapy—the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory ...(immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many deep learning-based methods have been proposed to handle complex single-cell data. Deep learning approaches may also prove useful to jointly analyze single-cell RNA sequencing (scRNA-seq) and ...single-cell T cell receptor sequencing (scTCR-seq) data for novel discoveries. We developed scNAT, a deep learning method that integrates paired scRNA-seq and scTCR-seq data to represent data in a unified latent space for downstream analysis. We demonstrate that scNAT is capable of removing batch effects, and identifying cell clusters and a T cell migration trajectory from blood to cerebrospinal fluid in multiple sclerosis.
Summary
Regulatory T cells are the central element for the maintenance of peripheral tolerance. Several subtypes of regulatory T (Treg) cells have been described, and most of them belong to the CD4+ ...T‐helper (Th) cell lineage. These specific subtypes can be discriminated according to phenotype and function. Forkhead box protein 3 (FoxP3)‐expressing natural Treg cells (Tregs) and IL‐10‐producing, T‐regulatory type 1 cells (Tr1) are the best‐studied types of CD4+ regulatory T cells in humans and experimental animal models. It was shown that they play a crucial role during autoimmune neuroinflammation. Both cells types seem to be particularly important for multiple sclerosis (MS). Here, we discuss the role of CD4+ regulatory T cells in autoimmune neuroinflammation with an emphasis on Tregs and Tr1 cells in MS.
CD4(+)CD25(high)CD127(low/-) forkhead box p3 (Foxp3)(+) regulatory T cells (T(reg) cells) possess functional plasticity. Here we describe a higher frequency of T helper type 1 (T(H)1)-like, ...interferon-γ (IFN-γ)-secreting Foxp3(+) T cells in untreated subjects with relapsing remitting multiple sclerosis (RRMS) as compared to healthy control individuals. In subjects treated with IFN-β, the frequency of IFN-γ(+)Foxp3(+) T cells is similar to that in healthy control subjects. In vitro, human T(reg) cells from healthy subjects acquire a T(H)1-like phenotype when cultured in the presence of interleukin-12 (IL-12). T(H)1-like T(reg) cells show reduced suppressive activity in vitro, which can partially be reversed by IFN-γ-specific antibodies or by removal of IL-12.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Fingolimod for Multiple Sclerosis Pelletier, Daniel; Hafler, David A
The New England journal of medicine,
01/2012, Letnik:
366, Številka:
4
Journal Article
Recenzirano
A 37-year-old man with multiple sclerosis has recurrent disease activity despite several previous therapies. Treatment with fingolimod is recommended. Fingolimod blocks the egress of lymphocytes from ...lymph nodes, preventing them from reaching the central nervous system.
Foreword
This
Journal
feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations.
Stage
A 37-year-old man with multiple sclerosis was evaluated for consideration of oral immunotherapy. Six years earlier, he had reported acute monocular visual disturbance. The diagnosis of multiple sclerosis was subsequently confirmed by means of examination of cerebrospinal fluid, which revealed an increased IgG index and oligoclonal banding, and by abnormal results on magnetic resonance imaging (MRI). There was no family history of multiple sclerosis. Daily injections of glatiramer acetate were initiated at the time of diagnosis, but two consecutive annual brain MRI scans revealed substantial disease activity. He was then switched to interferon beta therapy, but this treatment was . . .
Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human ...T(Reg) cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human T(Reg) cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human T(Reg) cells, including the ontogeny and development of T(Reg) cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by T(Reg) cell subsets and factors that regulate T(Reg) cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human T(Reg) cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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